PBR targeted agents for both tumor nuclear imaging and therapy

Objectives Peripheral benzodiazepine receptor PBR overexpression has been observed in a large variety of human cancers such as ovarian, colon-rectum and breast carcinomas. PK11195, an isoquinoline analog, is one of the PBR ligands of highest PBR binding affinity. Due to the long biological half life of our photosensitizers, there is a need to label it with a longer lived radioisotope. In our present study, our objectives were (i) to synthesize Iodinated-PK11195 and to compare its PBR binding affinity with that of unmodified PK11195, (ii) synthesize and characterize conjugates of one of the chlorophyll-a based photosensitizers developed in our laboratory with I-PK11195 for both imaging (PET) and Photodynamic therapy (PDT), (iii) in vitro and in vivo studies were performed.

Methods I-PK11195 and four of its conjugates with pyropheophorbide-a were synthesized. After investigating their PBR binding affinities, I-PK11195 and one of the conjugates of high PBR binding affinity was converted into the corresponding ¹²⁴I-derivatives. Serial PET imaging of colon-26 and EMT-6tumor bearing mice was performed using a high-resolution scanner (microPET Focus 120^®). Comparative in vitro and in vivo PDT efficacy investigations were also performed.

Results Excellent tumor localization of both ¹²⁴I-labeled PK11195 and the conjugate was observed. Compared to pyropheophorbide-a, conjugates with PK11195 showed improved its PBR binding affinity, target specificity and PDT efficacy.

Conclusions I-PK11195 can be a good vehicle to deliver the desired photosensitizers to PBR over-expressed tumor regions. Such conjugates could be useful for both tumor imaging (PET) and PDT.